Technology Spotlight:
DNA Display – Evolving a Better Drug

Deoxyribonucleic Acid (DNA) encodes the instructions to build every living organism, from E. coli to humans and everything in between. The genetic alphabet of DNA consists of just four letters that are used to write the genetic code which serves as a blueprint for assembling an organism. So why not use a DNA blueprint to build new drugs? Inventors Pehr Harbury and David Halpin have harnessed the basic DNA alphabet to write a different code. Instead of assembling an organism, the DNA Display code can be used for assembling small molecules on a laboratory bench.

The process begins with a library of special DNA sequences; each with a chemical building site attached to the end. Then, step-by-step, using the DNA sequence to guide the synthesis, a series of different chemical or enzymatic reactions is performed on the building site. Repeating this for four or more rounds creates a library of small molecules, each attached to its distinctive set of DNA instructions. The small molecules that make the best candidates for new drugs are then selected from the chemical library.

Amplify and Iterate for the Best Results
But that is only the beginning. Because each compound was synthesized using a genetic blueprint, the DNA sequences from promising compounds can be amplified, mixed and matched to “evolve” a molecule with even better characteristics (for example, tighter binding or enhanced specificity). In each subsequent generation, the properties of the synthetic compounds are refined. At the end of this iterative process, the entire small molecule library consists of good drug candidates that can easily be identified and recreated by reading the attached DNA instructions.

Libraries of a quadrillion compounds can be encoded, synthesized and screened with this technique by an individual scientist on a standard laboratory bench without the use of technically advanced equipment. Although this approach was designed with drug discovery in mind, it can also be used to develop novel industrial catalysts or research reagents.

“Genius”
If you think that this invention sounds like it might be the work of a genius, there are others who agree with you. For his work in this area, Dr. Harbury recently received a prestigious National Institutes of Health Director’s Pioneer Award and a MacArthur Fellowship – an honor frequently called a “genius grant.”

The MacArthur Award will join a mantle full of other national awards Dr. Harbury has received. He has received the 2004 Schering-Plough Young Investigator Award, the Searle Scholar Young Investigator Award, and a Burroughs-Wellcome Young Investigator Award. He was also named one of 100 Young Innovators by MIT’s Technology Review magazine in 1999.

For more information about licensing the DNA Display invention, contact Kirsten Leute at kirsten.leute@stanford.edu, (650) 723-4374.